Human Adenoviruses Infection and Kidney Transplantation: Pathogenesis, Diagnosis, and Treatment

Introduction

Human adenoviruses (HAdV), belonging to the Adenoviridae family, are nonenveloped, icosahedral viruses containing double-stranded DNA. Initially isolated from adenoid tissue in the 1950s, HAdVs have since been implicated in respiratory infections, exhibiting a broad spectrum of human diseases [1, 2]. Presently, HAdVs are associated with a myriad of human diseases. There exist one hundred and three distinct genotypes of human adenoviruses classified into seven primary serotypes, denoted as A through G, predicated upon the hemagglutinin properties of their fiber protein and genomic homology. By the age of six, at least 80% of the general populace demonstrates seropositivity to one serotype. While adenoviral infections are frequently asymptomatic and self-limiting, fatal outcomes can arise in immunocompromised individuals, including both pediatric and adult populations. The incidence of infection is notably higher in young children compared to adults, predominantly affecting the upper respiratory tract but also capable of inducing pneumonia. Among adults, heightened risk is observed in individuals residing in close quarters and those with compromised immune systems [2–5]. Transmission modalities encompass inhalation of aerosolized droplets, direct conjunctival inoculation, fecal-oral spread, and contact with infected biological materials. The incubation period varies contingent upon the viral serotype and mode of transmission, spanning from 2 days to 2 weeks. HAdVs can establish lifelong asymptomatic infections within lymphoepithelial tissues, renal parenchyma, tonsils, adenoids, and the gastrointestinal tract [2]. Several studies have indicated a lack of seasonal pattern in AdV infections. Immunocompromised individuals bear a heightened burden of severe HAdV-associated manifestations, encompassing gastrointestinal, ophthalmological, genitourinary, and neurological complications, along with heightened risk of graft loss [2, 5–7].

The administration of induction therapy poses a considerable risk of infectious morbidity and mortality in the burgeoning population of solid organ transplant (SOT) recipients. Although infrequent, HAdV infections have been documented across all SOT populations, with the highest incidence recorded among intestinal, pulmonary, and renal transplant recipients. Asymptomatic HAdV viremia is not uncommon among SOT recipients, occurring in an estimated 7.2% of cases within the initial year post-transplantation [1]. However, HAdV infections can progress to severe or disseminated disease in this cohort. In addition to immunosuppressive drugs, pivotal risk factors contributing to disease progression include patient age, malnutrition, underlying chronic conditions, and the type of transplanted organ [8, 9].

Kidney transplantation stands as the definitive therapeutic recourse for patients afflicted with end-stage renal diseases. However, this intervention renders recipients susceptible to symptomatic HAdV infection. Approximately 6.5% of kidney transplant recipients exhibit HAdV viremia. The heightened susceptibility of kidney transplant recipients stems from the immunosuppressed state induced by induction therapy, coupled with the propensity of select HAdV serotypes to establish latent infections within renal cells. Predominant adenovirus subgroups linked with renal pathologies include B1 and B2, encompassing serotypes 3, 7, 16, 21, and 50 within B1 and 11, 14, and 55 within B2. Serotypes 7 and 11 are most commonly detected in kidney transplant recipients [2]. Although symptomatic adenoviral infections are rare, severe disseminated adenovirus infections correlate with an elevated risk of adverse transplant outcomes, such as rejection, ventricular dysfunction, allograft vasculopathy, graft loss, and necessitating re-transplantation [10]. Due to its infrequent occurrence and nonspecific symptomatology, Adenoviruses are not routinely screened in transplant donors or receievers [11]. Therefore, patients are frequently misdiagnosed with acute rejection, urinary tract infections, drug toxicity, or other viral infections, underscoring the necessity for further elucidation of the pathogenesis, clinical manifestations, diagnostic modalities, and therapeutic interventions for this infection.

 

Pathogenesis

The pathogenesis of HAdV infection within renal tissue is multifaceted and encompasses several sequential stages. Initial viral attachment involves the interaction between the viral fiber protein and specific cellular receptors expressed on the surface of renal cells. While the Coxsackie and Adenovirus Receptor (CAR) serve as the primary receptor for most HAdV serotypes, serotypes 7, 11, 14, and 55 utilize Desmoglein-2 (DSG2) as their primary receptor [12]. Both receptors are expressed on the apical surface of the epithelium of many organs, including the kidney [13, 14]. Upon binding of the fiber protein trimers to these receptors, viral internalization occurs via dynamin-mediated endocytosis, facilitated by the formation of clathrin-coated pits on the cell membrane, subsequent vesicle formation, and acidification. The secretion of acid sphingomyelinase into lysosomes leads to an elevation in ceramide lipid levels, thereby augmenting several crucial processes within the context of adenoviral infection. Specifically, this elevation promotes enhanced virion endocytosis, facilitates the binding of the HAdV hexon protein to cellular membranes, and potentiates membrane rupture [15].

In the second stage of HAdV infection viral replication and gene expression ensue. Dynein and kinesin, components of the cytoskeletal system, are instrumental in transporting viral particles to the nucleus. The HAdV genome, characterized by a linear double-stranded DNA (dsDNA) molecule approximately 36 kilobasepairs (Kbps) in length, infiltrates the nucleus of renal cells. Within this intracellular compartment, the viral DNA undergoes transcription mediated by the host cell transcriptional machinery, leading to the generation of messenger RNA (mRNA). Subsequently, viral mRNA is translated into viral proteins. Early viral genes, expressed initially, encode proteins responsible for regulating viral gene expression and replication, notably including the E1A and E1B proteins. Conversely, late viral genes, expressed subsequently, encode structural proteins essential for the assembly of new viral particles. These structural proteins encompass the hexon, penton base, and fiber proteins, which collectively constitute new viral particles. The formation of these viral components finally elicits an immune response [16].

The third phase of HAdV infection following renal transplantation involves the activation of the immune system. HAdV-infected cells are identified as foreign by the immune system, which effectively eliminates the virus. This immune response entails the mobilization of T cells, B cells, and natural killer cells, collaborating to eradicate the virus-infected cells. However, in renal transplant recipients, the use of immunosuppressive drugs can hinder this immune response. Research indicates heightened oxidative stress and acute-phase inflammation in individuals with stages 3 to 5 chronic kidney disease when compared to healthy individuals [17]. This vulnerability creates a positive feedback loop between viral infection and immune-mediated responses in individuals with kidney injury. In the kidney, inflammation is orchestrated by resident tubular cells and often involves inflammatory cells, particularly macrophages [18]. The molecular mechanism driving inflammation associated with HAdV is intricate, primarily characterized by the activation of proinflammatory cytokines and chemokines. These include tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) [19]. Furthermore, induction of apoptosis represents one mechanism employed by HAdVs to induce cell death, involving autophagy and autophagy-induced caspase activity [20, 21]. These processes manifest in the histopathological findings of post-transplant events which will be discussed later in this paper.

The fourth and final stage of HAdV infection in renal transplantation is the clinical manifestation of disease. Through the mentioned pathogenesis/immunopathogenesis pathways, HAdV infection can cause a wide range of clinical symptoms in immunocompromised patients.

 

Clinical Manifestations

Although most HAdV infections resolve on their own, those affecting immunocompromised individuals can be severe or even fatal, particularly if the virus disseminates systemically [22]. HAdV is responsible for a range of illnesses, including keratoconjunctivitis, pharyngoconjunctival fever, pneumonia, gastroenterocolitis, tracheopharyngitis, interstitial pneumonitis, myocarditis, hepatitis, interstitial nephritis, meningoencephalitis, and hemorrhagic cystitis [1, 22]. The majority of infections occurring outside the urinary tract have the potential to advance and lead to clinically significant illness, occasionally resulting in death [2].

The predominant urologic manifestation following kidney transplantation is acute hemorrhagic cystitis, with approximately 11% of patients excreting HAdV in the first year post-transplantation. If a patient with HAdV infection does not present with hemorrhagic cystitis, suspicion of HAdV may not arise, posing challenges for diagnosis [1, 22]. Patients experiencing hemorrhagic cystitis typically exhibit symptoms such as fever, dysuria, urgency, frequency, gross hematuria, and voiding complaints. In some cases, hemorrhagic cystitis can advance to involve the kidney, potentially resulting in graft dysfunction and granulomatous interstitial nephritis. Despite reducing immunosuppression, symptoms may persist for several weeks, emphasizing the importance of close monitoring of blood and urinary viral load [2, 22]. In the vast majority of patients, renal function typically returns to baseline following the resolution of HAdV infection [22].

Many individual case reports have documented instances of HAdV nephritis. Additionally, it has been noted that the majority of patients presenting with hemorrhagic cystitis exhibit concurrent acute graft dysfunction. Histological examination reveals tubulitis alongside tubular destruction, necrosis, and observable viral cytopathic effects within the renal tubules [22].

The categorized data of 10 case reports from October 2017 to October 2023 can be seen in Table 1. It shows some of rare and infrequent symptoms and clinical manifestations of post kidney transplantation HAdV infection along with usual manifestations and findings.

Author/Year	Outcome	Treatment	Imaging Findings	HAdV PCR Sample	Laboratory Findings	Pathology Findings	Transplant/ Onset	Diagnosis	First Presentations
Sanathkumar et al., 2023 [23]	Died shortly after onset	Stent replacement, Broad-spectrum antibiotics	Ultrasound: Normal	Peripheral blood	Microscopic hematuria	Necrosis, Thrombotic microangiopathy, hyperchromatic smudged nuclei, cortical necrosis, interstitial hemorrhage	KT   16 days	Renal artery thrombosis, Ureter necrosis, Graft dysfunction	Urinary leak, fever
Mihaylov et al., 2022 [8]	Died 72h post-admission	None	CT: Moderate hepatic steatosis	Liver biopsy, Blood serology	↑Creatinine, ↑Liver enzymes, Hyperkalemia	Extensive necrosis	KT   25 days	Severe acute liver/kidney failure	General malaise, fever, leukopenia
Fujita et al., 2022 [24]	Discharged	↓IMs, MZ discontinued, ↓MP, ↓Tacrolimus, IVIG	Normal	Urine	Hypovolemia, Proteinuria, Non-glomerular hematuria	FSGS, Tubular atrophy, Interstitial inflammation, Severe tubulitis, C4d+	KT   4.5 years	Pyuria, AKI, Hemorrhagic cystitis	Persistent fever, painful urination, bladder irritation, gross hematuria
Watanabe et al., 2021 [1]	Discharged	↓Immunosuppressant	CT: Hypoperfused mass lesions	Urine (-), Sera/kidney biopsy (+)	↑CRP	Necrotizing granuloma, Interstitial hemorrhage, Severe tubulitis, Smudgy nuclei	KT   21 months	Acute lobar nephritis	Sore throat, fever
Saliba et al., 2019 [25]	Discharged	↓Immunosuppression, No antimicrobials	US: Normal; CT: Enlarged graft, cortical hypodensity	Blood	Leukopenia, Lymphopenia, Microscopic hematuria, ↑Creatinine	60% necrosis, Thrombotic microangiopathy, Interstitial fibrosis, Tubular atrophy, Viral inclusions	KT   14 days	Mild graft dysfunction	High-grade fever, urinary frequency, dysuria
Sudhindra et al., 2019 [26]	Discharged	MMF discontinued, ↓Tacrolimus 25%, IVIG, CDV, Brincidofovir	CXR: Right lower lobe infiltrate	Nasopharyngeal swab	↑Creatinine	None	KT   12 years	Acute hypoxemic respiratory failure	Cough, nasal congestion, sore throat, fever
Moreira et al., 2019 [27]	Discharged	Ganciclovir, IVIG, Valganciclovir	US: Normal	Serum, urine, renal biopsy	Microscopic hematuria, Leucocyturia	Granulomatous interstitial nephritis, Ground-glass nuclei	KT   17 days	Renal dysfunction	Fever, diarrhea
Alquadan et al., 2018 [28]	Discharged	Mycophenolate held, IVIG, CDV	None	Bronchial washings, urine	↑Creatinine	Severe interstitial inflammation, Tubulitis	KT 16 months	AKI	Fever, hematuria, respiratory decline
Seralathan et al., 2017 [29]	Discharged	↓Immunosuppressants	None	Tubular epithelial cells	↑Creatinine, Hematuria	Cortical edema, Medullary inflammation, Tubular necrosis, Ruptured basement membranes, Smudged nuclei	KT   23 days	Interstitial nephritis	Blood clots in urine
Hemmersbach et al., 2018 [30]	Discharged	↓Immunosuppressants, CMX-001	PET-CT: Prostate/spleen uptake	Blood, urine	Leukopenia, ↑Creatinine, Microscopic hematuria	None	Liver-Kidney   5 months	Disseminated HAdV	Fever, headache, fatigue, anorexia, abdominal tenderness
Xu et al., 2018 [10]	Discharged	↓Immunosuppressants, CDV	None	Serum, renal biopsy	↑Creatinine	Pyelonephritis	Heart-Kidney   3 years	Hemorrhagic cystitis, AKI, Respiratory failure	Fever, nausea, vomiting, cough, urinary incontinence, leukocytosis

Table 1. Case reports of adenoviral infection in kidney allograft patients (2017-2023). HAdV: Adenovirus, PCR: Polymerase Chain Reaction, KT: Kidney Transplant, AKI: Acute Kidney Injury, FSGS: Focal Segmental Glomerulosclerosis, IM: Immunosuppressive Medications, MZ: Mizoribine, MP: Methylprednisolone, IVIG: Intravenous Immunoglobulin, CRP: C-reactive protein, CT: computed tomography, NA: Not Available, CXR: chest X-ray, MMF: mycophenolate mofetil, CDV: cidofovir, PET-CT: Positron emission tomography–computed tomography.

 

Paraclinical Findings

Prompt diagnosis and timely intervention are crucial in halting disease progression and enhancing patient prognosis. HAdV infections may manifest with diverse clinical symptoms. In severe instances, patients could develop pneumonia, hepatitis, or disseminated disease. Diagnosis of HAdV in kidney transplantation usually entails a blend of histopathological examination, laboratory assessments, and imaging studies, complementing clinical evaluations.

Histopathology Findings

Microscopic examination findings offer crucial insights into the underlying pathology of HAdV-associated kidney diseases, as direct cytopathic effects represent one of the mechanisms by which HAdVs inflict damage on the kidney. Additionally, immune-mediated injury and thrombotic microangiopathy play significant roles in kidney injury during adenoviral infection [23, 31, 32]. Several studies have documented the direct cytopathic effects of HAdV on renal tubular cells. These effects typically manifest as smudgy basophilic intranuclear inclusions with enlarged nuclei in infected cells. Distal tubules are more frequently affected than proximal tubules, although occasional involvement of glomerular visceral and parietal epithelial cells can also occur. Associated with these changes is acute tubular injury, often accompanied by tubular necrosis and destruction, as well as acute interstitial nephritis characterized by a pleomorphic infiltrate consisting of lymphocytes, histiocytes, plasma cells, and varying numbers of neutrophils, alongside interstitial edema and hemorrhage. Tubular destruction may be accompanied by necrotizing interstitial granulomas, with severe granulomatous tubulointerstitial nephritis being a characteristic feature of HAdV infection and relatively rare in other viral infections. Focal wedge-shaped necrosis can also be observed in renal parenchyma. HAdV in renal tubular cells can be detected using immunohistochemistry and in situ hybridization techniques. Immunostaining for HAdV typically reveals strong nuclear and cytoplasmic staining in infected cells, which may also exhibit nuclear condensation, cytoplasmic vacuolation, and loss of brush border [33].

Electron microscopy of urine samples or kidney tissue is also valuable for detecting adenoviral infection. Viral particles can be observed within infected epithelial nuclei and cytoplasm. These particles typically appear nonenveloped with a hexagonal outline and a diameter ranging from 70 to 110 nm. They often aggregate in a crystalline array (Figure 1) [34].

Figure 1. A: A ×80,000 magnified picture of HAdV serotype 5 particles. The particles measure 75-80 nm in diameter and are arranged in crystalline arrays (Credit to F. A. Murphy, University of Texas Medical Branch, Galveston, Texas [35]). B: A ×20 magnified and hematoxylin–eosin stained picture showing necrosis and interstitial hemorrhage due to HAdV infection in kidney of a autopsied patient (Takashi Abe et al., Hemodialysis – Different Aspects [36]). C: A ×40 magnified and hematoxylin–eosin stained picture showing Cowdry A, full-type and smudge-type inclusion bodies in affected tubules (Takashi Abe et al., Hemodialysis – Different Aspects [36]).

In terms of differential diagnosis, acute cellular rejection typically exhibits a T cell-dominant interstitial infiltrate without viral cytopathic changes within tubular epithelial cells. The presence of vascular rejection featuring endothelialitis serves as a diagnostic hallmark for T cell-mediated rejection, even in the context of confirmed HAdV infection through immunostaining. Polyomavirus-related cytopathic changes can sometimes overlap with HAdV-related cytopathic changes. Polyomavirus nephropathy often presents with a more plasma cell-rich pleomorphic infiltrate, devoid of interstitial hemorrhage, and nuclei of infected tubular epithelial cells typically exhibit strong staining for simian virus 40 (SV40). Granulomatous interstitial nephritis is exceptionally rare in polyomavirus nephropathy. In contrast, hantavirus infection tends to feature a predominantly mononuclear cell interstitial infiltrate with interstitial hemorrhages, accompanied by viral cytopathic changes but without HAdV immunostaining positivity. Tuberculosis infection is characterized by multifocal necrotizing granulomatous interstitial nephritis, with special stains revealing positivity for acid-fast bacilli. Acute pyelonephritis typically presents with a marked, predominantly neutrophilic interstitial infiltrate, with neutrophil plugs observed within tubules but without viral cytopathic changes. Acute interstitial nephritis due to drug-induced hypersensitivity reactions may exhibit a higher frequency of interstitial eosinophils, lacking viral cytopathic changes and showing negative HAdV immunostaining [34].

In most cases, histopathology findings do not provide a definitive diagnosis. However, they are necessary to confirm and determine the extent of damage to the kidneys.

Laboratory Findings

The laboratory findings associated with HAdV renal involvement can vary depending on the severity of the infection and the stage at which the patient is evaluated. Some common laboratory findings include:

• Urinalysis: Urine analysis within the initial 14 days following kidney transplantation plays a crucial role in determining the outcome of the allograft [37]. Comprehending the difficulties inherent in each phase following kidney transplantation is essential for laboratorians. The urine albumin to creatinine ratio (ACR) serves as a straightforward and efficient metric for forecasting graft function post-transplantation. It demonstrates robust independent correlations with creatinine clearance akin to those of serum creatinine, eliminating the need for a blood draw [38]. Hematuria, proteinuria, and pyuria serve as significant indicators of renal function in patients with HAdV-associated kidney infection. Research has shown that the severity of these complications often correlates with the extent of renal damage. However, it’s important to note that these findings alone are not specific indicators of HAdV [37]. The primary causes of proteinuria following kidney transplantation include treatment with mammalian target inhibitors of rapamycin, antibody-mediated rejection of the allograft, and exposure to toxic agents. Additionally, it’s crucial to recognize that proteinuria post-transplantation can originate from either the allograft itself or the native kidney [39]. Hematuria is prevalent in approximately 12% of patients following renal transplantation [37]. Urinary tract infections represent a significant cause of hematuria. Thus, it is advisable to conduct a urine culture to exclude the involvement of other pathogens [40]. In general, in renal transplantation patients, sterile hematuria or pyuria may suggest the presence of genitourinary pathogens that conventional urine culture methods cannot detect.
• Nucleic acid tests (NATs): NATs stand as the most precise diagnostic options. Research has shown a correlation between increasing or high-level viremia and the risk of both invasive disease and mortality [41]. Polymerase chain reaction (PCR), real-time PCR (qPCR), and loop-mediated isothermal amplification (LAMP) are all viable methods for detecting and typing adenoviruses, depending on the requirements of the study. Among NATs, PCR is the most commonly available test in healthcare facilities. HAdV can be detected by PCR in various specimens including urine, stool or rectal swab, whole blood, plasma, cerebrospinal fluid (CSF), and bronchoalveolar lavage (BAL). Many commercial PCR test kits utilize the hexon gene as the detection marker, boasting sensitivities and specificities exceeding 90%. Early specimen collection in the clinical course and prompt shipment under cold chain can enhance detection rates [42].
• Immunological tests: These tests detect the presence of antibodies to adenoviruses or viral antigens in a patient’s serum. Commercially available immunological tests for adenoviruses include Enzyme-Linked Immunosorbent Assay (ELISA), Immunofluorescence Assay (IFA), direct fluorescent antigen (DFA), enzyme immunoassay (EIA), and western blot. Antigen assays are particularly useful in epidemiological studies. They are also the preferred method for detecting the fastidious HAdV types 40 and 41 in stool samples [43]. Indirect immunofluorescence assays can be employed for the direct examination of tissue specimens and are accessible through commercial laboratories. However, it’s crucial to recognize that antibody-detecting methods hold limited clinical value due to the common occurrence of seroreactivity to HAdV. By the age of 4 years, roughly half of all children have positive HAdV titers [44]. If a serologic diagnosis is pursued, it is recommended to obtain serum samples as early as possible in the clinical course, followed by a second titer 2-4 weeks later. A diagnostic indicator is a fourfold increase in acute titers compared to convalescent titers [45].
• Complete Blood Count (CBC): The CBC can provide valuable insights into estimating the risk of developing renal injury and mortality. Parameters such as anemia, leukopenia, leukocytosis, and thrombocytopenia can help gauge the severity of illness. Additionally, markers derived from routine blood analysis, including the neutrophil-to-lymphocyte ratio (NLR), neutrophil, lymphocyte, and platelet ratio (NLPR), and platelet-to-lymphocyte ratio (PLR), offer simple and effective means of predicting outcomes related to renal injury across various clinical settings [46]. Viral infections can produce diverse effects on the CBC. While there is currently no specific study demonstrating the impact of HAdVs in renal transplantation, it has been observed that these viruses can elevate the monocyte ratio during respiratory infections [47].
• Liver Function Tests (LFTs): HAdVs have been associated with causing acute hepatitis in immunocompromised individuals [48]. This is especially prominent in pediatric liver transplantation cases [49]. However, it can affect all patients due to induction therapy and systemic HAdV infection. The signs and symptoms of HAdV hepatitis resemble those of other viral infections and typically include markedly elevated aminotransferase levels and severe coagulopathy [50]. Therefore, LFTs are good monitoring modalities for disseminated HAdV infection post kidney transplantation.
• Acute phase reactants: Acute phase reactants are inflammation markers that undergo significant changes in serum concentration during inflammation, often in response to an infection. The diagnostic utility of acute phase reactants relies on factors such as the condition of the host tissue and the characteristics of the pathogen involved [51]. C-reactive protein (CRP) is the most well-known acute phase reactant. Its expression is up-regulated in various human viral infections. CRP levels typically begin to rise after 12-24 hours and peak within 2-3 days. In noninfectious “metabolic inflammatory” conditions, a “high sensitivity CRP” assay may detect low levels of CRP elevation, typically ranging between 2 and 10 mg/L [52].  Procalcitonin is another acute phase reactant that, under normal conditions, is secreted by the C-cells of the thyroid gland in response to hypercalcemia or as a result of medullary carcinoma of the thyroid. Normally, serum concentrations of PCT are < 0.05 ng/mL. PCT levels become detectable within 3-4 hours and peak within 6-24 hours, which is earlier than CRP. PCT secretion is stimulated by various inflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor-alpha [53]. In viral infections, the production of PCT is typically reduced, likely due to increased interferon-gamma production. Therefore, PCT demonstrates higher sensitivity in distinguishing between bacterial and viral infections [54]. Apolipoproteins, haptoglobin, hemopexin, hepcidin, ferritin, and ceruloplasmin are among the additional acute phase reactants that could indicate virus-mediated inflammation. However, they currently have less clinical value and require further studies before being incorporated into commercial laboratory assays [55].

Imaging Studies

Imaging studies may not always be essential for diagnosing HAdV-associated kidney infection, particularly in mild cases. However, in severe instances or when complications are suspected, imaging studies can offer valuable insights for diagnosis and management. Ultrasound imaging may reveal high resistive indices in the upper pole, which are associated with a heightened risk of graft loss and morbidity, as well as the presence of hydronephrosis in confirmed infection cases [55]. Computed tomography (CT) is another valuable imaging modality for detecting kidney abnormalities in patients with HAdV infection. CT scans can reveal lesions on the allograft and confirm the presence of hydronephrosis [56].

It is important to note that for each individual case of HAdV-associated renal damage comprehensive evaluation by a healthcare professional is necessary to determine the most appropriate diagnostic and treatment approach.

 

Treatment

While HAdV infection is typically self-limiting in the majority of the human population, it can present as an opportunistic infection in individuals with suppressed immune systems. Consequently, the primary treatment for patients with organ transplants, who regularly take immunosuppressive medications, involves reducing or discontinuing immunosuppression. However, there is no definitive therapeutic protocol for HAdV infection in SOT patients. Decisions regarding which immunosuppressive agent to reduce and the degree of reduction should be carefully discussed by the transplant and transplant infectious diseases teams, as clear guidelines are currently lacking [2, 22]. Reduced immunosuppression is typically continued until undetectable viral loads are achieved or until persistent low-level viral loads in the urine remain stable for several weeks. Reduction in viral load in the blood or urine is typically observed within two weeks [2]. As a routinly accepted practice, factors such as lack of clinical improvement, onset of hemorrhagic cystitis, and acute kidney injury are taken into consideration when deciding to temporarily discontinue administration of immunosuppressive agents and initiate antiviral therapy [10].

Even in cases of symptomatic HAdV hemorrhagic cystitis and transplant nephritis with viremia, reduction of immunosuppression is often sufficient for most patients. Due to the significant toxicity associated with alternative agents, antiviral medications are typically reserved for patients with progressive or life-threatening infections. When therapy is deemed necessary, most clinicians opt for cidofovir (CDV) despite its potential toxicity. CDV must be administered intravenously and can be dosed at 5 mg/kg every 1-2 weeks or 1 mg/kg three times per week [2]. CDV is a cytosine nucleoside analog that functions as an inhibitor of viral DNA synthesis. Despite its off-label use as a therapeutic agent for serious HAdV disease, CDV has been associated with clinical benefits. However, there are significant drawbacks to this drug that severely limit its usefulness. CDV has low bioavailability, requiring higher doses to achieve adequate serum concentrations for clinical efficacy. Additionally, the rapid uptake but slow release of CDV from tubular kidney cells contributes to significant nephrotoxicity [7]. In general, CDV toxicities include nephrotoxicity, myelosuppression, and uveitis. To mitigate renal toxicity, it is crucial to ensure that the patient receives adequate hydration around dosing, with at least 500 mL of normal saline administered before and after infusions. Additionally, it is recommended to administer 2 g of probenecid 3 hours before, and 1 g 2 and 8 hours after CDV administration to further reduce the risk of nephrotoxicity [2].  A review of 228 case reports indicated that CDV was the most frequently administered antiviral treatment. Other cases involved the use of ribavirin, ganciclovir, and brincidofovir. Brincidofovir was utilized as salvage therapy in 12.2% of patients in instances of renal toxicity from CDV or when there was an unsatisfactory clinical response [57]. To mitigate much of the toxicity associated with cidofovir and enable oral delivery, brincidofovir was developed as a lipid ester prodrug of CDV. While it is currently approved for the treatment of smallpox, brincidofovir has also been used under compassionate use and in clinical studies against HAdV. Brincidofovir exhibits increased in vitro efficacy against HAdV and is associated with reduced renal and bone marrow toxicity compared to CDV. It boasts excellent oral bioavailability, allowing for once to twice weekly dosing, and demonstrates exceptional cellular penetration. Among patients treated with brincidofovir, the mean time to viral clearance was 4 weeks in those who responded to therapy. The primary side effect of the medication is diarrhea, which appears to be dose-dependent. If clinically available, brincidofovir may be the preferred choice for treating clinically significant adenoviral infections due to its improved safety profile compared to CDV. The duration of antiviral therapy depends on the clearance of detectable virus and clinical response [2].  Ribavirin has demonstrated little, if any, evidence of improving the outcomes of HAdV infections. Similarly, ganciclovir, originally developed for the treatment of herpesvirus infections, has shown limited efficacy as a therapeutic agent against HAdV. This is not surprising, as ganciclovir requires activation by a viral thymidine kinase to exert its maximal effectiveness, a feature that HAdV lacks [7].

Nitazoxanide may exhibit some activity against HAdV as it targets the protein replication process of the virus. Limited in vitro data suggest that it may be useful for treating enteritis or mild to moderate disease, particularly in the outpatient setting. Additionally, while most cases of HAdV-associated conjunctivitis are self-limited, N-chlorotaurine, an antimicrobial agent, has been demonstrated to shorten the duration of illness in cases of endemic keratoconjunctivitis [2]. There is no established benefit for intravenous immunoglobulin (IVIG) in the treatment of HAdV infection in transplant recipients. However, the use of HAdV- and multivirus-specific T-cell infusions is emerging as a promising therapeutic approach. These therapies are better tolerated, associated with fewer toxicities, and may even confer a mortality benefit [2].  Therapeutic approaches for the treatment of HAdV nephritis are similar to those for hemorrhagic cystitis, which are two of the most common clinical manifestations of HAdV infection. This typically involves reducing immunosuppression and providing supportive therapy [22].

 

Developing Therapeutic Options

Nanoparticle-based therapies

Nanoparticles offer several distinct advantages that can be utilized to enhance the effectiveness of antiviral medications. Payloads encapsulated within nanoparticles experience reduced exposure to the external environment, which can protect them from systemic degradation while also reducing cytotoxicity. Additionally, nanoparticles can improve the pharmacokinetic profiles of existing antiviral drugs by prolonging circulation time, targeting specific tissue locations, and enhancing bioavailability [58]. There are at least two directions of studies that can be highlighted in nanoparticle research for antiviral purposes. The first direction involves nanoparticles modified with various organic molecules. These functionalized nanoparticles can impact viruses through chemical interactions between the functionalizing molecules and receptors on the virus surface. The second direction focuses on the antiviral activity of non-functionalized nanoparticles. A study by Lysenko et al. in 2018 investigated the use of two types of gold nanoparticles, each covered with a SiO₂ shell and located on a larger nanoparticle carrier, as antiviral agents against HAdVs. It was found that these complex nanoparticles exhibited strong antiviral effects without being accumulated in living cells, demonstrating the non-toxic nature of such antiviral nanoparticles [59].

RNA-based therapies

RNA-based therapy refers to the utilization of RNA molecules to modulate biological pathways for curing specific conditions. This approach offers several advantages, including the ability to target traditionally untargetable genetic components, rapid design and synthesis, long-lasting effects when modifications are applied to their production or encapsulated by carrier components, suitability for rare diseases, and notably low genotoxicity. There are four major classes of RNA-based therapy: Antisense oligonucleotide (ASO), small interfering RNA (siRNA), aptamers, and mRNA. Currently, ASOs have been developed against various viruses including SARS-CoV-2, Dengue virus, respiratory syncytial virus, influenza, Ebola virus, hepatitis B virus, and HIV. ASOs have the potential to directly act against viral genomic RNA or transcripts and can be designed for various viral diseases ranging from acute to persistent infections. Therefore, ASOs represent a rational therapeutic option for HAdV infections in renal transplantation [60]. siRNAs, typically consisting of 21-23 base pairs, are powerful molecular tools for silencing target genes and inhibiting viral infections. A study conducted by A. Eckstein et al. in 2010 demonstrated that siRNA-mediated knockdown of genes expressed during the late phase of HAdV replication is effective in inhibiting HAdV replication. Furthermore, the study found that combining siRNAs targeting early and late HAdV genes can enhance the efficiency of anti-HAdV activity. This highlights the potential of siRNAs as a promising approach for combating HAdV infections [61]. Indeed, while other RNA-based options have not yet been extensively studied for HAdV infections, their success and cost-effectiveness against numerous viral infections make them promising candidates for future research.

Monoclonal antibodies

Monoclonal antibodies are synthetic molecules created in laboratories, capable of selectively targeting particular proteins and neutralizing their effects, such as the hexon or fiber proteins found in HAdVs. Research has verified that among HAdV serotypes 3, 5, 7, 14, or 55, the hexon protein serves as the primary target for neutralizing antibodies [62]. The specific neutralization sites on hexon proteins across various adenoviruses have been identified mainly within seven highly variable regions. Moreover, a study conducted by X. Tian et al. in 2018 revealed that the recombinant HAdV serotype 11 fiber knob can prompt the production of cross-neutralizing antibodies against several subgroups of type B HAdVs, including serotypes 11, 7, 14, and 55, in mice [63]. Monoclonal antibodies offer distinct advantages due to their specificity and effectiveness, coupled with the ability to be rapidly and abundantly manufactured. Consequently, they serve as a valuable resource for addressing conditions requiring swift interventions.

 

Conclusion

HAdVs represent a subset of pathogens within the Adenoviridae family, characterized by their icosahedral shape and nonenveloped structure. These viruses have double-stranded DNA genomes and are associated with a broad spectrum of human diseases, ranging from mild respiratory infections to severe illnesses such as pneumonia, gastroenteritis, and conjunctivitis. The extensive genetic diversity among HAdVs is reflected in the existence of 103 distinct genotypes, further classified into seven main serotypes (A through G). This classification is primarily based on variations in the hemagglutinin properties of their fiber protein and genomic homology.

While many infections caused by HAdVs  are asymptomatic or self-limiting, certain populations are at heightened risk, including individuals undergoing kidney transplantation. Among the numerous serotypes, B1 and B2 are particularly noteworthy for their propensity to target and infect the kidneys, potentially leading to renal injury and dysfunction. Diagnosing HAdV infections often involves a multifaceted approach, including histopathological examination of tissue biopsies, laboratory tests such as urine analysis, CBC, LFTs, acute phase proteins, immunoligal test and NATs, and imaging studies like computed ultrasonography and CT. Treatment strategies for HAdV infections typically focus on supportive care and immune system support. However, advancements in antiviral therapy offer promising alternatives. Agents such as Cidofovir and Nitazoxanide have shown efficacy against HAdVs, and ongoing research explores novel therapeutic modalities, including nanoparticle- and siRNA-based drugs, as well as monoclonal antibodies targeting specific viral components.

 

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